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1.
Proc Natl Acad Sci U S A ; 115(19): 4998-5003, 2018 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-29691324

RESUMO

CD58 is an adhesion molecule that is known to play a critical role in costimulation of effector cells and is intrinsic to immune synapse structure. Herein, we describe a virally encoded gene that inhibits CD58 surface expression. Human cytomegalovirus (HCMV) UL148 was necessary and sufficient to promote intracellular retention of CD58 during HCMV infection. Blocking studies with antagonistic anti-CD58 mAb and an HCMV UL148 deletion mutant (HCMV∆UL148) with restored CD58 expression demonstrated that the CD2/CD58 axis was essential for the recognition of HCMV-infected targets by CD8+ HCMV-specific cytotoxic T lymphocytes (CTLs). Further, challenge of peripheral blood mononuclear cells ex vivo with HCMV∆UL148 increased both CTL and natural killer (NK) cell degranulation against HCMV-infected cells, including NK-driven antibody-dependent cellular cytotoxicity, showing that UL148 is a modulator of the function of multiple effector cell subsets. Our data stress the effect of HCMV immune evasion functions on shaping the immune response, highlighting the capacity for their potential use in modulating immunity during the development of anti-HCMV vaccines and HCMV-based vaccine vectors.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Evasão da Resposta Imune , Imunidade Celular , Células Matadoras Naturais/imunologia , Proteínas Virais de Fusão/imunologia , Linfócitos T CD8-Positivos/patologia , Linhagem Celular Transformada , Citomegalovirus/genética , Infecções por Citomegalovirus/genética , Infecções por Citomegalovirus/patologia , Humanos , Células Matadoras Naturais/patologia , Proteínas Virais de Fusão/genética
2.
Breast Cancer Res Treat ; 163(3): 475-484, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28349272

RESUMO

PURPOSE: The basal-A subtype of triple-negative breast cancer is characterized by high levels of ΔNp63. Various functions have been proposed for p63 in breast cancer initiation and growth, and p63 mediates chemotherapeutic response in a subset of triple-negative breast cancers. We investigated the signaling pathways that are controlled by ΔNp63 in basal-A triple-negative breast cancer. METHODS: Human basal-A triple-negative breast cancer cell lines with ΔNp63α induction or inhibition were studied, along with primary human triple-negative breast cancer tissues. Proteomic, phospho-kinase array, mRNA measurements, and immunohistochemistry were employed. RESULTS: Global phosphoproteomics identified increased EGFR phosphorylation in MDA-MB-468 cells expressing ΔNp63α. ΔNp63α expression increased EGFR mRNA, total EGFR protein, and phospho-EGFR(Y1086), whereas silencing endogenous ΔNp63 in HCC1806 cells reduced both total and phospho-EGFR levels and inhibited the ability of EGF to activate EGFR. EGFR pathway gene expression analysis indicated that ΔNp63 alters EGFR-regulated genes involved in cell adhesion, migration, and angiogenesis. Addition of EGF or neutralizing EGFR antibodies demonstrated that EGFR activation is responsible for ΔNp63-mediated loss of cellular adhesion. Finally, immunohistochemical staining showed that p63-positive triple-negative breast cancers were more likely to express high levels of EGFR than p63-negative cancers, corroborated by in silico analysis of gene expression profiling data. CONCLUSIONS: These data identify EGFR as a major target for ΔNp63 regulation that influences cancer cell adhesion in basal-like triple-negative breast cancer.


Assuntos
Fator de Crescimento Epidérmico/genética , Receptores ErbB/genética , Proteínas de Membrana/genética , Neoplasias de Mama Triplo Negativas/genética , Adesão Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Fator de Crescimento Epidérmico/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica/genética , Metástase Neoplásica , Proteômica , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia
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